CA2719243C - Benzophenone thiazole derivatives useful for inhibiting formation of microtubule and method for producing the same - Google Patents
Benzophenone thiazole derivatives useful for inhibiting formation of microtubule and method for producing the same Download PDFInfo
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Abstract
Disclosed are a novel thiazole-containing benzophenone derivative represented by formula 1, and an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof, a pharmaceutical composition comprising the derivative, a use of the derivative as therapeutic agent and a method for preparing the derivative. The benzophenone thiazole derivatives inhibit formation of microtubules and eliminate actively proliferating cells of malignant tumors to control general cell proliferation. In formula 1, R, R1 and R2 are defined as above.
Description
[DESCRIPTION]
[Invention Title]
BENZOPHENONE THIAZOLE DERIVATIVES USEFUL FOR INHIBITING
FORMATION OF MICROTUBULE AND METHOD FOR PRODUCING THE SAME
[Technical Field]
The present invention relates to a thiazole-containing benzophenone derivative useful for inhibiting formation of microtubule, or an isomer thereof, a pharmaceutically 1 0 acceptable salt thereof, a hydrate thereof or a solvate thereof, a pharmaceutical composition comprising the derivative, a use of the derivative as a therapeutic agent and a method for preparing the derivative. The benzophenone thiazole derivatives of the present invention inhibit formation of microtubules, eliminate actively proliferating cells of malignant tumors and thus control general cell proliferation.
[Background Art]
The applicants of the present invention disclose novel benzophenone derivatives having inhibitory activity upon microtubule formation in Korean Patent No. 10-0094019 (filed on Sep. 27, 2006), Korean Patent No. 10-2007-0083856 (filed on Aug.
[Invention Title]
BENZOPHENONE THIAZOLE DERIVATIVES USEFUL FOR INHIBITING
FORMATION OF MICROTUBULE AND METHOD FOR PRODUCING THE SAME
[Technical Field]
The present invention relates to a thiazole-containing benzophenone derivative useful for inhibiting formation of microtubule, or an isomer thereof, a pharmaceutically 1 0 acceptable salt thereof, a hydrate thereof or a solvate thereof, a pharmaceutical composition comprising the derivative, a use of the derivative as a therapeutic agent and a method for preparing the derivative. The benzophenone thiazole derivatives of the present invention inhibit formation of microtubules, eliminate actively proliferating cells of malignant tumors and thus control general cell proliferation.
[Background Art]
The applicants of the present invention disclose novel benzophenone derivatives having inhibitory activity upon microtubule formation in Korean Patent No. 10-0094019 (filed on Sep. 27, 2006), Korean Patent No. 10-2007-0083856 (filed on Aug.
2 0 21, 2007) claiming the benefit thereof and PCT Application No.
(filed on Sep. 21, 2007).
Among the compounds disclosed in PCT/KR2007/004625, 516[ {4-(2-aminothiazol-4-y1)-2-(1H-1 ,2,4-tri azol-1- yl)pheny11 (3 ,4,5-trimethoxyphenyl)methanone]
is found to exhibit potent mitosis inhibitory activity and cytotoxicity. From animal test results, it can be confirmed that the toxicity is caused by deposition on organs due to its low solubility.
Accordingly, the inventors of the present invention attempted to develop compounds which exhibit more efficacious pharmaceutical effects and low toxicity via improvement in solubility of benzophenone derivatives, resulting in the present invention. That is, the present invention provides novel benzophenone thiazole compounds, as derivatives of 516[ (4-(2-aminothiazol-4-y1)-2-(1H-1,2,4-triazol-ypphenyll(3,4,5-trimethoxyphenyl)methanone], having efficient mitosis inhibition, superior antitumor activity, and improved solubility and thus considerably decreased toxicity.
[Disclosure]
[Technical Problem]
Therefore, the present invention has been made in view of the above problems, and it is one object of the present invention to provide a compound which is toxic to directly or indirectly active mitotic cells and is useful for treating malignant tumors, viral and bacterial infection, recurrent vascular occlusion, inflammatory diseases, autoimmune diseases and psoriasis.
Accordingly, the present invention provides a novel benzophenone thiazole 2 0 derivative useful for inhibiting formation of microtubules, or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
It is another object of the present invention to provide a pharmaceutical composition, as an active ingredient, comprising a benzophenone derivative containing thiazole useful for inhibiting formation of microtubules, or an isomer thereof, a 2 5 pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
It is yet another object of the present invention to provide a method for preparing a benzophenone derivative containing thiazole useful for inhibiting formation of microtubules, or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
[Technical Solution]
In accordance with the present invention, the above and other objects can be accomplished by the provision of a compound represented by formula 1 or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
Ri 11101 0 N'R2 lo ,õ0S (1) wherein R1 and R2 are each independently hydrogen (H) or methyl (CH3); and R
is hydrogen, methyl, ethyl, or one selected from compounds represented by the following moieties, in which R1 and R2 are joined together to form a ring:
NNZ
VtfLa tilArtft "VNs NH2 trt.rvw µ CA 02719243 2010-09-21 µ , s 0 NE12 NH2 N-=\
.7\''0 titniin NH2 HN,17 NH2 ..--) 7 NH 0 ---)OH
% 01111 OH
,..... NH
,SH
tnArvi Examples of preferred compounds represented by formula 1 are shown in Table 1 below:
= N = <N,N
Compound 0 Compound _AD
,---NH
_AD S ,-0 S
N¨A VN
0 % N = N
Compound 0 Compound 0 \
625 o 0 10 N O NI-12 631 40 * N .ito -1 )--NH 411 0 1 "¨NH
,0 , CA 02719243 2010-09-21 , ' , .N
= N
0 ip 646 Compound õõ 0 O N
Compound ,0 C .4..
i.), N
= kN.N
Compound , = i Compound õ.0 ......
a NH2 648 1, 0 0 NH2 ft \\
Ks N
0 N' Compound 23, s'O'-y-- N
_._NH i) ,r--i --- S
In accordance with another aspect of the present invention, provided is a pharmaceutical composition for inhibiting formation of microtubules, comprising the compound of formula 1 or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient or carrier.
Hereinafter, the method for preparing the compound will be illustrated in detail.
The compound of formula 1 may be prepared in accordance with a method disclosed in a variety of documents (Nguyen-Hai Nam et al., Bioorg. Med. Chem.
2003, 11, 1021; Rebecca Braslau et al., Org. Lett. 2000, 10, 1399; Akira Oku et al., J. Org.
Chem. 1986, 19, 3732; Francois Clemence et al., J. Med. Chem. 1988, 7, 1453;
Yu Su et al., Org. Lett. 2005, 7, 367). The preparation method of the compound of formula 1 will be illustrated in detail with reference to the following Reaction Scheme I:
[Reaction Scheme I]
(filed on Sep. 21, 2007).
Among the compounds disclosed in PCT/KR2007/004625, 516[ {4-(2-aminothiazol-4-y1)-2-(1H-1 ,2,4-tri azol-1- yl)pheny11 (3 ,4,5-trimethoxyphenyl)methanone]
is found to exhibit potent mitosis inhibitory activity and cytotoxicity. From animal test results, it can be confirmed that the toxicity is caused by deposition on organs due to its low solubility.
Accordingly, the inventors of the present invention attempted to develop compounds which exhibit more efficacious pharmaceutical effects and low toxicity via improvement in solubility of benzophenone derivatives, resulting in the present invention. That is, the present invention provides novel benzophenone thiazole compounds, as derivatives of 516[ (4-(2-aminothiazol-4-y1)-2-(1H-1,2,4-triazol-ypphenyll(3,4,5-trimethoxyphenyl)methanone], having efficient mitosis inhibition, superior antitumor activity, and improved solubility and thus considerably decreased toxicity.
[Disclosure]
[Technical Problem]
Therefore, the present invention has been made in view of the above problems, and it is one object of the present invention to provide a compound which is toxic to directly or indirectly active mitotic cells and is useful for treating malignant tumors, viral and bacterial infection, recurrent vascular occlusion, inflammatory diseases, autoimmune diseases and psoriasis.
Accordingly, the present invention provides a novel benzophenone thiazole 2 0 derivative useful for inhibiting formation of microtubules, or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
It is another object of the present invention to provide a pharmaceutical composition, as an active ingredient, comprising a benzophenone derivative containing thiazole useful for inhibiting formation of microtubules, or an isomer thereof, a 2 5 pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
It is yet another object of the present invention to provide a method for preparing a benzophenone derivative containing thiazole useful for inhibiting formation of microtubules, or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
[Technical Solution]
In accordance with the present invention, the above and other objects can be accomplished by the provision of a compound represented by formula 1 or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
Ri 11101 0 N'R2 lo ,õ0S (1) wherein R1 and R2 are each independently hydrogen (H) or methyl (CH3); and R
is hydrogen, methyl, ethyl, or one selected from compounds represented by the following moieties, in which R1 and R2 are joined together to form a ring:
NNZ
VtfLa tilArtft "VNs NH2 trt.rvw µ CA 02719243 2010-09-21 µ , s 0 NE12 NH2 N-=\
.7\''0 titniin NH2 HN,17 NH2 ..--) 7 NH 0 ---)OH
% 01111 OH
,..... NH
,SH
tnArvi Examples of preferred compounds represented by formula 1 are shown in Table 1 below:
= N = <N,N
Compound 0 Compound _AD
,---NH
_AD S ,-0 S
N¨A VN
0 % N = N
Compound 0 Compound 0 \
625 o 0 10 N O NI-12 631 40 * N .ito -1 )--NH 411 0 1 "¨NH
,0 , CA 02719243 2010-09-21 , ' , .N
= N
0 ip 646 Compound õõ 0 O N
Compound ,0 C .4..
i.), N
= kN.N
Compound , = i Compound õ.0 ......
a NH2 648 1, 0 0 NH2 ft \\
Ks N
0 N' Compound 23, s'O'-y-- N
_._NH i) ,r--i --- S
In accordance with another aspect of the present invention, provided is a pharmaceutical composition for inhibiting formation of microtubules, comprising the compound of formula 1 or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient or carrier.
Hereinafter, the method for preparing the compound will be illustrated in detail.
The compound of formula 1 may be prepared in accordance with a method disclosed in a variety of documents (Nguyen-Hai Nam et al., Bioorg. Med. Chem.
2003, 11, 1021; Rebecca Braslau et al., Org. Lett. 2000, 10, 1399; Akira Oku et al., J. Org.
Chem. 1986, 19, 3732; Francois Clemence et al., J. Med. Chem. 1988, 7, 1453;
Yu Su et al., Org. Lett. 2005, 7, 367). The preparation method of the compound of formula 1 will be illustrated in detail with reference to the following Reaction Scheme I:
[Reaction Scheme I]
0 SOCl2 or oxely1 chloride 0 0 ISOC12 or milli chloride vrvityliliRrtoc 0101F, MC, Refl ux DMF,141C Reflux 0 itN,N
0 cifi DMA, Pyridine 0 1 ,0 1111 N 3 or 5 ______ n W". R
Rom or Cli3 616 R2= H or CH3 14¨a k.
Piperidine, DM E R1 \01Y) -Nri In Reaction Scheme I, Fmoc is an N-a-9-fluorenylmethoxycarbonyl group, DIPEA is diisopropylethylamine, MC is methylene chloride, ph is phenyl, DMF is N,N-dimethylformamide, and R, RI and R2 are defined as above.
In accordance with Reaction Scheme I, thionyl chloride (S0C12) or oxalyl chloride is added to a compound of formula 2 or a compound of formula 4 as a starting material, respectively, to prepare a compound of formula 3 or a compound of formula 5, the compound of formula 3 or 5 reacts with a compound 516[ {4-(2-aminothiazol-4-y1)-2-( 1 H- 1 ,2,4-triazol- 1 -yl)phenyll (3 ,4,5-trimethoxyphenyl)methanone]
to prepare a 1 0 compound of formula 6, and de-protection reaction is performed.
[BRIEF DESCRIPTION OF THE DRAWINGS]
The above and other objects, features and other advantages of the present , , , , invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
FIG. 1 is a graph showing tumor volume on each administration day of compound 516, as a result of pharmaceutical effect tests of the compound 516 using a human-derived colorectal cancer cell line (CX-1);
FIG. 2 is a graph showing tumor volume on each administration day of compounds 624, 625 and 631, as a result of pharmaceutical effect tests of the compounds using a human-derived colorectal cancer cell line (CX-1);
FIG. 3 is a graph showing tumor volume on each administration day of 1 0 compound 624, as a result of pharmaceutical effect tests of the compound 624 using a human-derived colorectal cancer cell line (HCT-15);
FIG. 4 is a graph showing tumor volume on each administration day of compound 624, as a result of pharmaceutical effect tests of the compound 624 using a human-derived lung cancer cell line (A549);
FIG. 5 is a graph showing tumor volume on each administration day of compound 624, as a result of pharmaceutical effect tests of the compound 624 using a human-derived stomach cancer cell line (MKN45); and FIG. 6 is a graph showing tumor volume on each administration day of compound 624, as a result of pharmaceutical effect tests of the compound 624 using a 2 0 human-derived non-small cell lung cancer cell line (calu-6).
[Best Mode]
Now, the present invention will be described in more detail with reference to the following examples, preparation examples and experimental examples. These examples are provided only to illustrate the present invention. The scope of the claims should not be. limited to the preferred embodiments set forth in the examples herein but should be given the broadest interpretation consistent with the Description as a whole.
Example 1: Synthesis of compound 615 Synthesis of N-(4-(3-(1H-1,2.4-triazol-l-y1)-4-(3,4,5-trimethoxybenzoyDphenyl) thiazol-2-y1)-2-aminoacetamide Fmoc-glycine (0.94 g, 3.16 mrool) and N,N-dimethylformamide (one drop) were dissolved in methylene chloride (5 mL), thionyl chloride (S0C12, 0.3 mL) was added 1 0 thereto at ambient temperature and the resulting mixture was stirred under reflux for one hour. After the reaction was completed, the reaction solution was cooled to ambient temperature and was dried under reduced pressure to remove the solvent, the resulting compound (1 g) was added to a solution of the compound 516 (0.45 g, 1.07 mmol) in methylene chloride (10 mL) and pyridine (0.13 mL) and the resulting mixture was stirred 1 5 at ambient temperature overnight. After the reaction was completed, the resulting product was dried under reduced pressure to remove the solvent and purified by column chromatography (Si02; MC/Me0H 40/1-10/1) to obtain a solid compound (0.54 g, 71.6%). The resulting compound (0.46 g, 0.64 mmol) was dissolved in N,N-dimethylformamide (3 mL), piperidine (76 p.L) was added thereto at anabient temperature 2 0 and the resulting mixture was stirred at ambient temperature for 2 hours. After the reaction was completed, the resulting solution was dried under reduced pressure to remove the solvent and the resulting product was purified by column chromatography (Si02; MC/Me0H 20/1-5/1) to obtain a white solid compound 615 (246.6 mg, 77.9%).
II-1 NMR (400 MHz, acetone) & 8.790 (s, 1H), 8.372 (d, J= 1.48 Hz, 1H), 8.315 25 (dd, :1= 8.0, 1.6 Hz, 1H), 7.969 (s, 1H), 7.893 (s, 1H), 7.775 (d, .1=
0 cifi DMA, Pyridine 0 1 ,0 1111 N 3 or 5 ______ n W". R
Rom or Cli3 616 R2= H or CH3 14¨a k.
Piperidine, DM E R1 \01Y) -Nri In Reaction Scheme I, Fmoc is an N-a-9-fluorenylmethoxycarbonyl group, DIPEA is diisopropylethylamine, MC is methylene chloride, ph is phenyl, DMF is N,N-dimethylformamide, and R, RI and R2 are defined as above.
In accordance with Reaction Scheme I, thionyl chloride (S0C12) or oxalyl chloride is added to a compound of formula 2 or a compound of formula 4 as a starting material, respectively, to prepare a compound of formula 3 or a compound of formula 5, the compound of formula 3 or 5 reacts with a compound 516[ {4-(2-aminothiazol-4-y1)-2-( 1 H- 1 ,2,4-triazol- 1 -yl)phenyll (3 ,4,5-trimethoxyphenyl)methanone]
to prepare a 1 0 compound of formula 6, and de-protection reaction is performed.
[BRIEF DESCRIPTION OF THE DRAWINGS]
The above and other objects, features and other advantages of the present , , , , invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
FIG. 1 is a graph showing tumor volume on each administration day of compound 516, as a result of pharmaceutical effect tests of the compound 516 using a human-derived colorectal cancer cell line (CX-1);
FIG. 2 is a graph showing tumor volume on each administration day of compounds 624, 625 and 631, as a result of pharmaceutical effect tests of the compounds using a human-derived colorectal cancer cell line (CX-1);
FIG. 3 is a graph showing tumor volume on each administration day of 1 0 compound 624, as a result of pharmaceutical effect tests of the compound 624 using a human-derived colorectal cancer cell line (HCT-15);
FIG. 4 is a graph showing tumor volume on each administration day of compound 624, as a result of pharmaceutical effect tests of the compound 624 using a human-derived lung cancer cell line (A549);
FIG. 5 is a graph showing tumor volume on each administration day of compound 624, as a result of pharmaceutical effect tests of the compound 624 using a human-derived stomach cancer cell line (MKN45); and FIG. 6 is a graph showing tumor volume on each administration day of compound 624, as a result of pharmaceutical effect tests of the compound 624 using a 2 0 human-derived non-small cell lung cancer cell line (calu-6).
[Best Mode]
Now, the present invention will be described in more detail with reference to the following examples, preparation examples and experimental examples. These examples are provided only to illustrate the present invention. The scope of the claims should not be. limited to the preferred embodiments set forth in the examples herein but should be given the broadest interpretation consistent with the Description as a whole.
Example 1: Synthesis of compound 615 Synthesis of N-(4-(3-(1H-1,2.4-triazol-l-y1)-4-(3,4,5-trimethoxybenzoyDphenyl) thiazol-2-y1)-2-aminoacetamide Fmoc-glycine (0.94 g, 3.16 mrool) and N,N-dimethylformamide (one drop) were dissolved in methylene chloride (5 mL), thionyl chloride (S0C12, 0.3 mL) was added 1 0 thereto at ambient temperature and the resulting mixture was stirred under reflux for one hour. After the reaction was completed, the reaction solution was cooled to ambient temperature and was dried under reduced pressure to remove the solvent, the resulting compound (1 g) was added to a solution of the compound 516 (0.45 g, 1.07 mmol) in methylene chloride (10 mL) and pyridine (0.13 mL) and the resulting mixture was stirred 1 5 at ambient temperature overnight. After the reaction was completed, the resulting product was dried under reduced pressure to remove the solvent and purified by column chromatography (Si02; MC/Me0H 40/1-10/1) to obtain a solid compound (0.54 g, 71.6%). The resulting compound (0.46 g, 0.64 mmol) was dissolved in N,N-dimethylformamide (3 mL), piperidine (76 p.L) was added thereto at anabient temperature 2 0 and the resulting mixture was stirred at ambient temperature for 2 hours. After the reaction was completed, the resulting solution was dried under reduced pressure to remove the solvent and the resulting product was purified by column chromatography (Si02; MC/Me0H 20/1-5/1) to obtain a white solid compound 615 (246.6 mg, 77.9%).
II-1 NMR (400 MHz, acetone) & 8.790 (s, 1H), 8.372 (d, J= 1.48 Hz, 1H), 8.315 25 (dd, :1= 8.0, 1.6 Hz, 1H), 7.969 (s, 1H), 7.893 (s, 1H), 7.775 (d, .1=
8.12 Hz, 1H), 3.829-3.815 (s, 9H), 3.711 (s, 2H). (MS (ES1) m/z 495 (Ivr H).
Example 2: Synthesis of compound 624 (S)-N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-y1)-2-amino-3-methylbutanamide A white solid compound 624 (2.25 g, 53.2%) was obtained in the same manner as in the synthesis of the compound 615.
NMR (400MHz, CDC13) 6 8.338 (s, 1H), 8.172 (d, J = 1.52 Hz, 1H), 8.035 (dd, J= 8.08, 1.40 Hz, 1H), 7.937 (s, 1H), 7.653 (d, J= 8.08 Hz, 1H), 7.381 (s, 1H), 6.985 (s, 2H), 3.819 (s, 6H), 3.556 (d, J= 3.6 Hz, 1H), 2.481 (m, 1H), 1.092 (d, J= 6.96 Hz, 3H), 0.909 (d, J= 6.92 Hz, 3H). MS (ESI) m/z 537 (M+ + H).
Example 3: Synthesis of compound 625 Synthesis of (S)-N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl) phenypthiazol-2-y1)-2-amino-3-phenylpropanamide A white solid compound 625 (13.6 mg, 21.2%) was obtained in the same manner as in the synthesis of the compound 615.
NMR (400MHz, CDC13) 6 8.333 (s, 1H), 8.165 (d, J= 1.52 Hz, 1H), 7.935 (dd, J= 8.04, 1.52 Hz, 1H), 7.654 (d, J= 8.04 Hz, 1H), 7.405-7.245 (m, 6H), 6.985 (s, 2H), 3.903 (m, 4H), 3.819 (s, 6H), 3.389 (dd, J= 13.8, 3.72 Hz, 1H), 2.827 (m, 1H). MS
(ESI) m/z 585 (M+ + H).
Example 4: Synthesis of compound 631 Synthesis of N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl)phenyl) thiazol-2-y1)-2-(dimethylamino)acetamide /V,N-dimethylglycine (446.8 mg, 4.33 mmol) and /V,N-dimethylformamide (one drop) were dissolved in methylene chloride (5 mL), thionyl chloride (SOC12, 0.41 mL) was added thereto at ambient temperature and the resulting mixture was stirred at 70 C
for one hour. After the reaction was completed, the reaction solution was cooled to ambient temperature and dried under reduced pressure to remove the solvent to obtain a compound 5 as an intermediate. The compound 516 (94.6 mg, 0.22 mmol) was dissolved in methylene chloride (5 mL) and pyridine (26.2 IlL), the compound 5 (68.3 mg) was added thereto and the resulting mixture was stirred at ambient temperature overnight.
After the reaction was completed, the reaction solution was dried under reduced pressure to remove the solvent and the resulting product was purified by column chromatography (Si02, MC/Me0H 40/1-5/1) to obtain a brown compound 631 (24.1 mg, 21.3%).
11-1 NMR (400 MHz, acetone) 5 8.760 (s, 1H), 8.302 (d, J= 1.28 Hz, 1H), 8.231 (dd, J= 8.0, 1.6 Hz, 1H), 7.871 (s, 2H), 7.718 (d, J= 8.12 Hz, 1H), 6.995 (s, 2H), 3.796 (s, 6H), 3.785 (s, 3H), 3.000 (s, 2H), 2.430 (s, 6H). MS (ESI) m/z 523 (M+ +
H).
Example 5: Synthesis of compound 646 Synthesis of (S)-N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl) phenyl)thiazol-2-yppyrolidine-2-carboxamide A white solid compound 646 (7.8 mg, 25.1%) was obtained in the same manner as in the synthesis of the compound 615.
11-1 NMR (400 MHz, Me0D) 5 8.817 (s, 1H), 8.268 (m, 2 H), 7.940 (s, 1H), 7.845 (s, 1H), 7.744 (m, 1H), 6.970 (s, 2H), 4.068-4.037 (m, 1H), 3.826 (s, 3H), 3.789 (s, 6H), 3.181 (m, 1H), 2.686-2.617 (m, 1H), 2.344-2.263 (m, 1H), 2.344 (m, 1H), 2.005-1.841 (m, 3H). MS (ESI) m/z 535 (M+ + H).
Example 2: Synthesis of compound 624 (S)-N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-y1)-2-amino-3-methylbutanamide A white solid compound 624 (2.25 g, 53.2%) was obtained in the same manner as in the synthesis of the compound 615.
NMR (400MHz, CDC13) 6 8.338 (s, 1H), 8.172 (d, J = 1.52 Hz, 1H), 8.035 (dd, J= 8.08, 1.40 Hz, 1H), 7.937 (s, 1H), 7.653 (d, J= 8.08 Hz, 1H), 7.381 (s, 1H), 6.985 (s, 2H), 3.819 (s, 6H), 3.556 (d, J= 3.6 Hz, 1H), 2.481 (m, 1H), 1.092 (d, J= 6.96 Hz, 3H), 0.909 (d, J= 6.92 Hz, 3H). MS (ESI) m/z 537 (M+ + H).
Example 3: Synthesis of compound 625 Synthesis of (S)-N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl) phenypthiazol-2-y1)-2-amino-3-phenylpropanamide A white solid compound 625 (13.6 mg, 21.2%) was obtained in the same manner as in the synthesis of the compound 615.
NMR (400MHz, CDC13) 6 8.333 (s, 1H), 8.165 (d, J= 1.52 Hz, 1H), 7.935 (dd, J= 8.04, 1.52 Hz, 1H), 7.654 (d, J= 8.04 Hz, 1H), 7.405-7.245 (m, 6H), 6.985 (s, 2H), 3.903 (m, 4H), 3.819 (s, 6H), 3.389 (dd, J= 13.8, 3.72 Hz, 1H), 2.827 (m, 1H). MS
(ESI) m/z 585 (M+ + H).
Example 4: Synthesis of compound 631 Synthesis of N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl)phenyl) thiazol-2-y1)-2-(dimethylamino)acetamide /V,N-dimethylglycine (446.8 mg, 4.33 mmol) and /V,N-dimethylformamide (one drop) were dissolved in methylene chloride (5 mL), thionyl chloride (SOC12, 0.41 mL) was added thereto at ambient temperature and the resulting mixture was stirred at 70 C
for one hour. After the reaction was completed, the reaction solution was cooled to ambient temperature and dried under reduced pressure to remove the solvent to obtain a compound 5 as an intermediate. The compound 516 (94.6 mg, 0.22 mmol) was dissolved in methylene chloride (5 mL) and pyridine (26.2 IlL), the compound 5 (68.3 mg) was added thereto and the resulting mixture was stirred at ambient temperature overnight.
After the reaction was completed, the reaction solution was dried under reduced pressure to remove the solvent and the resulting product was purified by column chromatography (Si02, MC/Me0H 40/1-5/1) to obtain a brown compound 631 (24.1 mg, 21.3%).
11-1 NMR (400 MHz, acetone) 5 8.760 (s, 1H), 8.302 (d, J= 1.28 Hz, 1H), 8.231 (dd, J= 8.0, 1.6 Hz, 1H), 7.871 (s, 2H), 7.718 (d, J= 8.12 Hz, 1H), 6.995 (s, 2H), 3.796 (s, 6H), 3.785 (s, 3H), 3.000 (s, 2H), 2.430 (s, 6H). MS (ESI) m/z 523 (M+ +
H).
Example 5: Synthesis of compound 646 Synthesis of (S)-N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl) phenyl)thiazol-2-yppyrolidine-2-carboxamide A white solid compound 646 (7.8 mg, 25.1%) was obtained in the same manner as in the synthesis of the compound 615.
11-1 NMR (400 MHz, Me0D) 5 8.817 (s, 1H), 8.268 (m, 2 H), 7.940 (s, 1H), 7.845 (s, 1H), 7.744 (m, 1H), 6.970 (s, 2H), 4.068-4.037 (m, 1H), 3.826 (s, 3H), 3.789 (s, 6H), 3.181 (m, 1H), 2.686-2.617 (m, 1H), 2.344-2.263 (m, 1H), 2.344 (m, 1H), 2.005-1.841 (m, 3H). MS (ESI) m/z 535 (M+ + H).
. , Example 6: Synthesis of compound 647 Synthesis of (S)-N-(4-(3 -(1H-1 ,2,4-triazol-1 -y1)-4-(3,4,5-trimethoxyb enzoyl) phenypthiazol-2-y1)-2-amino-4-methylpentanamide A white solid compound 647 (8.5 mg, 23.6 %) was obtained in the same manner as in the synthesis of the compound 615.
111 NMR (400 MHz, CDC13) 8 8.311 (s, 1H), 8.105-8.055 (m, 2H), 7.942 (s, 1H), 7.649 (d, J = 7.96 Hz, 1H), 7.439 (s, 1H), 6.978 (s, 2H), 3.892 (s, 311), 3.814 (s, 6H), 3.742-3.725 (m, 1H), 1.999-1.925 (m, 2H), 1.508-1.462 (m, 1H), 1.018 (t, J= 5.96 Hz, 6H). MS (ESI) m/z 551 (M+ + H).
Example 7: Synthesis of compound 648 Synthesis of (S)-N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl) phenyl)thiazol-2-v1)-2-amino-3-cyclohexylpropane amide A white solid compound 648 (46.8 mg, 36%) was obtained in the same manner as in the synthesis of the compound 615.
Ifl NMR (400 MHz, CDC13) 8 8.305 (s, 1H), 8.099-8.049 (m, 2H), 7.936 (s, 1H), 7.643 (d, J = 8.04 Hz, 1H), 7.434 (s, 1H), 7.257 (s, 1H), 6.972 (s, 2H), 3.886 (s, 3H), 3.783-3.748 (m, 7H), 2.044-1.309 (m, 13H). MS (ESI) m/z 631 (M+ + 40).
Example 8: Synthesis of compound 652 Synthesis of N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyflphenyl) thiazol-2-y1)-2-amino-3 -methylbutanami de A white solid compound 652 (258.2 mg, 63.1%) was obtained using Fmoc-valine (racemic isomer) in the same manner as in the synthesis of the compound 615.
111 NMR (400 MHz, CDC13) 8 8.311 (s, 1H), 8.105-8.055 (m, 2H), 7.942 (s, 1H), 7.649 (d, J = 7.96 Hz, 1H), 7.439 (s, 1H), 6.978 (s, 2H), 3.892 (s, 311), 3.814 (s, 6H), 3.742-3.725 (m, 1H), 1.999-1.925 (m, 2H), 1.508-1.462 (m, 1H), 1.018 (t, J= 5.96 Hz, 6H). MS (ESI) m/z 551 (M+ + H).
Example 7: Synthesis of compound 648 Synthesis of (S)-N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyl) phenyl)thiazol-2-v1)-2-amino-3-cyclohexylpropane amide A white solid compound 648 (46.8 mg, 36%) was obtained in the same manner as in the synthesis of the compound 615.
Ifl NMR (400 MHz, CDC13) 8 8.305 (s, 1H), 8.099-8.049 (m, 2H), 7.936 (s, 1H), 7.643 (d, J = 8.04 Hz, 1H), 7.434 (s, 1H), 7.257 (s, 1H), 6.972 (s, 2H), 3.886 (s, 3H), 3.783-3.748 (m, 7H), 2.044-1.309 (m, 13H). MS (ESI) m/z 631 (M+ + 40).
Example 8: Synthesis of compound 652 Synthesis of N-(4-(3-(1H-1,2,4-triazol-1-y1)-4-(3,4,5-trimethoxybenzoyflphenyl) thiazol-2-y1)-2-amino-3 -methylbutanami de A white solid compound 652 (258.2 mg, 63.1%) was obtained using Fmoc-valine (racemic isomer) in the same manner as in the synthesis of the compound 615.
. .
, 1H NMR (400MHz, CDC13) 6 8.338 (s, 1H), 8.172 (d, J = 1.52 Hz, 1H), 8.035 (dd, J = 8.08, 1.40 Hz, 1H), 7.937 (s, 1H), 7.653 (d, J = 8.08 Hz, 1H), 7.381 (s, 1H), 6.985 (s, 2H), 3.819 (s, 6H), 3.556 (d, J= 3.6 Hz, 1H), 2.481 (m, 1H), 1.092 (d, J = 6.96 Hz, 3H), 0.909 (d, J= 6.92 Hz, 3H). MS (ESI) m/z 537 (M+ + H).
Example 9: Synthesis of compound 653 Synthesis of (R)-N-(4-(3 -(1H-1 ,2,4-triazol-1-y1)-4-(3,4,5-trimethoxyb enzoyl) phenyl)thi azol-2-y1)-2-amino-3 -methylbutanamide A white solid compound 653 (2.25 g, 53.2%) was obtained using Fmoc-D-valine in the same manner as in the synthesis of the compound 615.
111 NMR (400MHz, CDC13) 6 8.338 (s, 1H), 8.172 (d, J = 1.52 Hz, 1H), 8.035 (dd, J= 8.08, 1.40 Hz, 1H), 7.937 (s, 1H), 7.653 (d, J= 8.08 Hz, 1H), 7.381 (s, 1H), 6.985 (s, 2H), 3.819 (s, 6H), 3.556 (d, J= 3.6 Hz, 1H), 2.481 (m, 1H), 1.092 (d, J= 6.96 Hz, 3H), 0.909 (d, J= 6.92 Hz, 3H). MS (ESI) m/z 537 (M+ + H).
Experimental Example 1: Measurement of solubility in water The compounds of the present invention were developed to reduce toxicity caused by deposition on organ due to low solubility of compound 516, as confirmed by animal tests. Considering this, solubility of the present compounds in water was thus 2 0 measured.
(1) Test methods CD Determination of calibration line The compound was dissolved in acetonitrile to a concentration of 1 mg/mL and the solution was diluted with a mobile phase to a concentration of 5, 12.5, 25, 50 or 100 2 5 ,ughnt.
, 1H NMR (400MHz, CDC13) 6 8.338 (s, 1H), 8.172 (d, J = 1.52 Hz, 1H), 8.035 (dd, J = 8.08, 1.40 Hz, 1H), 7.937 (s, 1H), 7.653 (d, J = 8.08 Hz, 1H), 7.381 (s, 1H), 6.985 (s, 2H), 3.819 (s, 6H), 3.556 (d, J= 3.6 Hz, 1H), 2.481 (m, 1H), 1.092 (d, J = 6.96 Hz, 3H), 0.909 (d, J= 6.92 Hz, 3H). MS (ESI) m/z 537 (M+ + H).
Example 9: Synthesis of compound 653 Synthesis of (R)-N-(4-(3 -(1H-1 ,2,4-triazol-1-y1)-4-(3,4,5-trimethoxyb enzoyl) phenyl)thi azol-2-y1)-2-amino-3 -methylbutanamide A white solid compound 653 (2.25 g, 53.2%) was obtained using Fmoc-D-valine in the same manner as in the synthesis of the compound 615.
111 NMR (400MHz, CDC13) 6 8.338 (s, 1H), 8.172 (d, J = 1.52 Hz, 1H), 8.035 (dd, J= 8.08, 1.40 Hz, 1H), 7.937 (s, 1H), 7.653 (d, J= 8.08 Hz, 1H), 7.381 (s, 1H), 6.985 (s, 2H), 3.819 (s, 6H), 3.556 (d, J= 3.6 Hz, 1H), 2.481 (m, 1H), 1.092 (d, J= 6.96 Hz, 3H), 0.909 (d, J= 6.92 Hz, 3H). MS (ESI) m/z 537 (M+ + H).
Experimental Example 1: Measurement of solubility in water The compounds of the present invention were developed to reduce toxicity caused by deposition on organ due to low solubility of compound 516, as confirmed by animal tests. Considering this, solubility of the present compounds in water was thus 2 0 measured.
(1) Test methods CD Determination of calibration line The compound was dissolved in acetonitrile to a concentration of 1 mg/mL and the solution was diluted with a mobile phase to a concentration of 5, 12.5, 25, 50 or 100 2 5 ,ughnt.
=
Preparation of specimen 1. The compound was added to distilled water such that the concentration of each specimen was adjusted to 10 mg/mL, stirred in a thermostat stirrer (25 C, 200 rpm) for about 7 days, filtered and diluted with a mobile phase to an optimal concentration.
2. The compound was added to distilled water such that the concentration of each specimen was adjusted to 10 mg/mL, sonicated for 30 minutes, stirred for minutes, filtered, sonicated for 30 minutes again and diluted with a mobile phase to an optimal concentration.
(2) HPLC conditions UV: 215 nm Flow rate: 1 mL/mL
Amount injected: 10 ,tbe Column temperature: 25 C
Column: Kromasil C8 (4.6x150 mm, 5 tan) Mobile phase: 20 mM ammonium acetate, pH 5.0/ACN (60/40) (3) Test results The solubility of the compounds of the present invention was compared with that of the compound 516 and the results thus obtained are shown in Table 2 below.
Compound Compound Compound Compound Compound Compound Compound Compound Solubility 0.5 23.3 14.9 11.0 25.4 29.1 12.1 12.5 (mg/mL) As can be seen from Table 2 above, the compound 516 exhibited considerably low solubility of 0.5 mg/mL, while the compounds of the present invention exhibited high solubility of 10 mg/mL or higher, which are comparable to or higher than a currently available reference drug, AC7700 (See: Anticancer Drug Des. 1999, Dec;
Preparation of specimen 1. The compound was added to distilled water such that the concentration of each specimen was adjusted to 10 mg/mL, stirred in a thermostat stirrer (25 C, 200 rpm) for about 7 days, filtered and diluted with a mobile phase to an optimal concentration.
2. The compound was added to distilled water such that the concentration of each specimen was adjusted to 10 mg/mL, sonicated for 30 minutes, stirred for minutes, filtered, sonicated for 30 minutes again and diluted with a mobile phase to an optimal concentration.
(2) HPLC conditions UV: 215 nm Flow rate: 1 mL/mL
Amount injected: 10 ,tbe Column temperature: 25 C
Column: Kromasil C8 (4.6x150 mm, 5 tan) Mobile phase: 20 mM ammonium acetate, pH 5.0/ACN (60/40) (3) Test results The solubility of the compounds of the present invention was compared with that of the compound 516 and the results thus obtained are shown in Table 2 below.
Compound Compound Compound Compound Compound Compound Compound Compound Solubility 0.5 23.3 14.9 11.0 25.4 29.1 12.1 12.5 (mg/mL) As can be seen from Table 2 above, the compound 516 exhibited considerably low solubility of 0.5 mg/mL, while the compounds of the present invention exhibited high solubility of 10 mg/mL or higher, which are comparable to or higher than a currently available reference drug, AC7700 (See: Anticancer Drug Des. 1999, Dec;
14(6): 539-48).
Experimental Example 2: Pharmaceutical effects of the compound in mice (1) Test animal BALB/c male nude mice (4 weeks) available from Central Lab Animal Inc. were used for human xenograft experiments. Sterile food and potable water were freely provided to the mice in an isolated sterile cage and the temperature of the cage was maintained at 23 0.5 C.
(2) Cell lines A human cancer model, CX-1 (human colon adenocarcinoma), for xenograft experiment was obtained from the German Cancer Research Center (DKFZ), and HCT-(human colorectal adenocarcinoma, CCL-225) and A549 (human lung carcinoma, 15 CCL-185) were obtained from ATCC (American Type Culture Collection, Rockville, MD, USA). Human tumor cells, MKN45 (human gastric adenocarcinoma, #80103) and calu-6 (human lung carcinoma, #30056) were obtained from KCLB (Korean Cell Line Bank).
CX-1 was incubated in a 95% air incubator (37 C, 5% CO2) using a DMEM
2 0 (Dulbecco's Modified Eagle's Medium, Gibco) supplemented with 10% heat-inactivated fetal bovine serum (Gibco) and 1% Antibiotics-Antimycotics (Gibco). Other cell lines were incubated in a 95% air incubator (37 C, 5% CO2) using an RPM1640 (Gibco BRL) medium supplemented with 10% heat-inactivated fetal bovine serum (Gibco) and 1%
Antibiotics-Antimycotics (Gibco).
2 5 (3) In vivo antitumor activity In vivo human xenograft experiments were performed in accordance with the following procedure. In vitro proliferated human-derived cancer cell lines (CX-1, HCT-15, A549, MKN45, calu-6) were subcutaneously injected into the abdominal region of BALB/c nude mice and were thus proliferated in vivo. After 20 to 25 days, the mice were sacrificed by cervical spine dislocation, solid cancer cells proliferated in the mice were sterilely separated and fresh cancer cells from which connective or necrotic tissues or skin were removed were collected. The fragments of tumor were transplanted to the BALB/c nude mice.
The mice in which cancer cells were proliferated to a predetermined size were 1 0 collected on the 15th to 30th day after human-derived cancer models were transplanted into the BALB/c nude mice and then used for the tests. For each experimental group, the drug was injected at a dose of 0.1 mL per 10 g of mouse in accordance with a dose schedule, when tumor cells were grown to a size of 100 to 200 mm3 after tumor transplantation.
After administration, antitumor activity was evaluated based upon an antitumor inhibition rate (IR%) of tumor growth, obtained by comparing a tumor volume measured on the final day with a tumor volume of a control group. As the reference drug, AC7700 (Sanofi-Aventis), which is currently undergoing phase III clinical trials, was used.
2 0 Tumor size = (short diameter)2 x (long diameter)/2 IR.(%) = [1-(average tumor size of drug-administered group)/(average tumor size of control group)] x100 CD The results of pharmaceutical effect tests of the compound 516 using human-derived colorectal cancer model (CX-1) are shown in Table 3 below and FIG. 1.
2 5 FIG. 1 is a graph showing tumor volume on each administration day of compound 516.
, , Experimental Administration Body weight Number of Dose/day IR (%) group (n=6) method change (%) dead animals Control group +18.4 AC7700 100 mg/kg q4d x 4 (i. p.) +13.2 48% 2/6 Compound mg/kg q4d x 4 (i. p.) +15.2 36% 2/6 As can be seen from Table 3 above and FIG. 1, in the results of CX-1 xenograft model, the compound 516 exhibited significantly superior pharmaceutical effects, as 5 compared to the reference drug, AC7700, but two animals died on the 6th and 7th day due to strong toxicity in vivo, which indicates that the compound 516 has a considerably narrow safety margin.
2 The results of pharmaceutical effect tests of the compounds 624, 625 and 631 using human-derived colorectal cancer model (CX-1) are shown in Table 4 below 1 0 and FIG. 2. FIG. 2 is a graph showing tumor volume on each administration day of compounds 624, 625 and 631.
Experimental Administration Body weight Number of Dose/day IR (%) group (n=6) method change (%) dead animals Control group +24.5 AC7700 100 mg/kg q4d x 4 (i. p.) +22.8 34% 0/6 Compound 5 mg/kg+25.7 28%
q4d x 4 (i. p.) 624 10 mg/kg +14.7 64%
Compound 5 mg/kg+28.9 21%
625 10 mg/kg q4d x 4 (i. +24.5 p.) 43%
5 mg/kg +24.8 23%
Compound mg/kg q4d x 4 (i. p.) +26.7 20% 0/6 mg/kg +20.9 37%
As can be seen from Table 4 above and FIG. 2, in the result of CX-1 xenograft 1 5 model, the compounds 624, 625 and 631 exhibited significantly superior pharmaceutical effects, as compared to the reference drug, AC7700, underwent no weight loss, as , compared to the compound 516, and caused no animal death, which indicates that the compounds have considerably improved safety. In particular, the compound 624 exhibited double the pharmaceutical effects of the reference drug.
3 The results of pharmaceutical effect tests of the compound 624 using human-derived colorectal cancer model (HCT-15) are shown in Table 5 below and FIG.
3.
FIG. 3 is a graph showing tumor volume on each administration day of compound 624.
Experimental Administration Body weightNumber of Dose/day a (%) group (n=6) method change (%) dead animals Control group - - -3.4 AC7700 80 mg/kg q4d x 4 (i. p.) +5.5 66%
5 mg/kg +1.8 12%
Compound 7.5 mg/kg , q4d x 4 (i. p.) +3.2 63%
mg/kg +6.6 69% 0/6 As can be seen from Table 5 above and FIG. 3, in the result of additional HCT-10 15 xenograft model, the compound 624 also exhibited significantly superior pharmaceutical effects, as compared with the reference drug.
10 The results of pharmaceutical effect tests of the compound 624 using human-derived lung cancer model (A549) are shown in Table 6 below and FIG. 4.
FIG.
4 is a graph showing tumor volume on each administration day of compound 624.
Experimental Administration Body weight Number of Dose/day I.R. (%) group (n=7) method change (%) dead animals Control group - - +5.4 AC7700 80 mg/kg q4d x 4 (i. p.) +2.6 64%
5 mg/kg -1.7 39%
Compound 7.5 mg/kg q4d x 4 (i. p.) +1.7 61%
10 mg/kg -1.2 71%
Experimental Example 2: Pharmaceutical effects of the compound in mice (1) Test animal BALB/c male nude mice (4 weeks) available from Central Lab Animal Inc. were used for human xenograft experiments. Sterile food and potable water were freely provided to the mice in an isolated sterile cage and the temperature of the cage was maintained at 23 0.5 C.
(2) Cell lines A human cancer model, CX-1 (human colon adenocarcinoma), for xenograft experiment was obtained from the German Cancer Research Center (DKFZ), and HCT-(human colorectal adenocarcinoma, CCL-225) and A549 (human lung carcinoma, 15 CCL-185) were obtained from ATCC (American Type Culture Collection, Rockville, MD, USA). Human tumor cells, MKN45 (human gastric adenocarcinoma, #80103) and calu-6 (human lung carcinoma, #30056) were obtained from KCLB (Korean Cell Line Bank).
CX-1 was incubated in a 95% air incubator (37 C, 5% CO2) using a DMEM
2 0 (Dulbecco's Modified Eagle's Medium, Gibco) supplemented with 10% heat-inactivated fetal bovine serum (Gibco) and 1% Antibiotics-Antimycotics (Gibco). Other cell lines were incubated in a 95% air incubator (37 C, 5% CO2) using an RPM1640 (Gibco BRL) medium supplemented with 10% heat-inactivated fetal bovine serum (Gibco) and 1%
Antibiotics-Antimycotics (Gibco).
2 5 (3) In vivo antitumor activity In vivo human xenograft experiments were performed in accordance with the following procedure. In vitro proliferated human-derived cancer cell lines (CX-1, HCT-15, A549, MKN45, calu-6) were subcutaneously injected into the abdominal region of BALB/c nude mice and were thus proliferated in vivo. After 20 to 25 days, the mice were sacrificed by cervical spine dislocation, solid cancer cells proliferated in the mice were sterilely separated and fresh cancer cells from which connective or necrotic tissues or skin were removed were collected. The fragments of tumor were transplanted to the BALB/c nude mice.
The mice in which cancer cells were proliferated to a predetermined size were 1 0 collected on the 15th to 30th day after human-derived cancer models were transplanted into the BALB/c nude mice and then used for the tests. For each experimental group, the drug was injected at a dose of 0.1 mL per 10 g of mouse in accordance with a dose schedule, when tumor cells were grown to a size of 100 to 200 mm3 after tumor transplantation.
After administration, antitumor activity was evaluated based upon an antitumor inhibition rate (IR%) of tumor growth, obtained by comparing a tumor volume measured on the final day with a tumor volume of a control group. As the reference drug, AC7700 (Sanofi-Aventis), which is currently undergoing phase III clinical trials, was used.
2 0 Tumor size = (short diameter)2 x (long diameter)/2 IR.(%) = [1-(average tumor size of drug-administered group)/(average tumor size of control group)] x100 CD The results of pharmaceutical effect tests of the compound 516 using human-derived colorectal cancer model (CX-1) are shown in Table 3 below and FIG. 1.
2 5 FIG. 1 is a graph showing tumor volume on each administration day of compound 516.
, , Experimental Administration Body weight Number of Dose/day IR (%) group (n=6) method change (%) dead animals Control group +18.4 AC7700 100 mg/kg q4d x 4 (i. p.) +13.2 48% 2/6 Compound mg/kg q4d x 4 (i. p.) +15.2 36% 2/6 As can be seen from Table 3 above and FIG. 1, in the results of CX-1 xenograft model, the compound 516 exhibited significantly superior pharmaceutical effects, as 5 compared to the reference drug, AC7700, but two animals died on the 6th and 7th day due to strong toxicity in vivo, which indicates that the compound 516 has a considerably narrow safety margin.
2 The results of pharmaceutical effect tests of the compounds 624, 625 and 631 using human-derived colorectal cancer model (CX-1) are shown in Table 4 below 1 0 and FIG. 2. FIG. 2 is a graph showing tumor volume on each administration day of compounds 624, 625 and 631.
Experimental Administration Body weight Number of Dose/day IR (%) group (n=6) method change (%) dead animals Control group +24.5 AC7700 100 mg/kg q4d x 4 (i. p.) +22.8 34% 0/6 Compound 5 mg/kg+25.7 28%
q4d x 4 (i. p.) 624 10 mg/kg +14.7 64%
Compound 5 mg/kg+28.9 21%
625 10 mg/kg q4d x 4 (i. +24.5 p.) 43%
5 mg/kg +24.8 23%
Compound mg/kg q4d x 4 (i. p.) +26.7 20% 0/6 mg/kg +20.9 37%
As can be seen from Table 4 above and FIG. 2, in the result of CX-1 xenograft 1 5 model, the compounds 624, 625 and 631 exhibited significantly superior pharmaceutical effects, as compared to the reference drug, AC7700, underwent no weight loss, as , compared to the compound 516, and caused no animal death, which indicates that the compounds have considerably improved safety. In particular, the compound 624 exhibited double the pharmaceutical effects of the reference drug.
3 The results of pharmaceutical effect tests of the compound 624 using human-derived colorectal cancer model (HCT-15) are shown in Table 5 below and FIG.
3.
FIG. 3 is a graph showing tumor volume on each administration day of compound 624.
Experimental Administration Body weightNumber of Dose/day a (%) group (n=6) method change (%) dead animals Control group - - -3.4 AC7700 80 mg/kg q4d x 4 (i. p.) +5.5 66%
5 mg/kg +1.8 12%
Compound 7.5 mg/kg , q4d x 4 (i. p.) +3.2 63%
mg/kg +6.6 69% 0/6 As can be seen from Table 5 above and FIG. 3, in the result of additional HCT-10 15 xenograft model, the compound 624 also exhibited significantly superior pharmaceutical effects, as compared with the reference drug.
10 The results of pharmaceutical effect tests of the compound 624 using human-derived lung cancer model (A549) are shown in Table 6 below and FIG. 4.
FIG.
4 is a graph showing tumor volume on each administration day of compound 624.
Experimental Administration Body weight Number of Dose/day I.R. (%) group (n=7) method change (%) dead animals Control group - - +5.4 AC7700 80 mg/kg q4d x 4 (i. p.) +2.6 64%
5 mg/kg -1.7 39%
Compound 7.5 mg/kg q4d x 4 (i. p.) +1.7 61%
10 mg/kg -1.2 71%
As can be seen from Table 6 above and FIG. 4, in the result of additional A549 xenograft model, the compound 624 also exhibited significantly superior pharmaceutical effects, as compared with the reference drug.
0 The results of pharmaceutical effect tests of the compound 624 using human-derived stomach cancer model (MKN45) are shown in Table 7 below and FIG.
5.
FIG. 5 is a graph showing tumor volume on each administration day of compound 624.
Experimental Administration Body weight Number of (%) group (n=6) Dose/day method change (%) dead animals Control group -15.3 0/6 AC7700 80 mg/kg q4d x 4 (i. p.) +7.8 55% 0/6 5 mg/kg -11.8 21% 0/6 Compound 7.5 mg/kg q4d x 4 (i. p.) +2.9 46% 0/6 mg/kg +4.3 68% 0/6 As can be seen from Table 7 above and FIG. 5, in the result of additional 1 0 MKN45 xenograft model, the compound 624 also exhibited significantly superior pharmaceutical effects, as compared with the reference drug.
8 The results of pharmaceutical effect tests of the compound 624 using human-derived non-small cell lung cancer model (calu-6) are shown in Table 8 below and FIG. 6. FIG. 6 is a graph showing tumor volume on each administration day of compound 624.
Experimental Administration Body weight Number of Dose/day IR (%) group (n=6) method change (%) dead animals Control group +30.0 0/6 AC7700 80 mg/kg q4d x 4 (i. p.) +22.4 80% 0/6 5 mg/kg +26.2 41% 0/6 Compound 7.5 mg/kg q4d x 4 (i. p.) +26.0 73% 0/6 10 mg/kg +20.6 82% 0/6 As can be seen from Table 8 above and FIG. 6, in the result of additional calu-xenogaft model, the compound 624 also exhibited significantly superior pharmaceutical effects, as compared with the reference drug.
[Industrial Applicability]
As apparent from the fore-going, the benzophenone thiazole derivative of the present invention inhibits formation of microtubules and eliminates actively proliferating cells of malignant tumors, thus being useful as therapeutic agents for malignant tumors, viral and bacterial infection, recurrent vascular occlusion, inflammatory diseases, autoimmune diseases and psoriasis.
0 The results of pharmaceutical effect tests of the compound 624 using human-derived stomach cancer model (MKN45) are shown in Table 7 below and FIG.
5.
FIG. 5 is a graph showing tumor volume on each administration day of compound 624.
Experimental Administration Body weight Number of (%) group (n=6) Dose/day method change (%) dead animals Control group -15.3 0/6 AC7700 80 mg/kg q4d x 4 (i. p.) +7.8 55% 0/6 5 mg/kg -11.8 21% 0/6 Compound 7.5 mg/kg q4d x 4 (i. p.) +2.9 46% 0/6 mg/kg +4.3 68% 0/6 As can be seen from Table 7 above and FIG. 5, in the result of additional 1 0 MKN45 xenograft model, the compound 624 also exhibited significantly superior pharmaceutical effects, as compared with the reference drug.
8 The results of pharmaceutical effect tests of the compound 624 using human-derived non-small cell lung cancer model (calu-6) are shown in Table 8 below and FIG. 6. FIG. 6 is a graph showing tumor volume on each administration day of compound 624.
Experimental Administration Body weight Number of Dose/day IR (%) group (n=6) method change (%) dead animals Control group +30.0 0/6 AC7700 80 mg/kg q4d x 4 (i. p.) +22.4 80% 0/6 5 mg/kg +26.2 41% 0/6 Compound 7.5 mg/kg q4d x 4 (i. p.) +26.0 73% 0/6 10 mg/kg +20.6 82% 0/6 As can be seen from Table 8 above and FIG. 6, in the result of additional calu-xenogaft model, the compound 624 also exhibited significantly superior pharmaceutical effects, as compared with the reference drug.
[Industrial Applicability]
As apparent from the fore-going, the benzophenone thiazole derivative of the present invention inhibits formation of microtubules and eliminates actively proliferating cells of malignant tumors, thus being useful as therapeutic agents for malignant tumors, viral and bacterial infection, recurrent vascular occlusion, inflammatory diseases, autoimmune diseases and psoriasis.
Claims (7)
1. A compound represented by formula 1 below or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein R1 and R2 are each independently hydrogen (H) or methyl (CH3); and R
is joined with R1 or R2 to form a 5-membered ring, or R is hydrogen, methyl, ethyl, or one selected from the group consisting of the following moieties:
wherein R1 and R2 are each independently hydrogen (H) or methyl (CH3); and R
is joined with R1 or R2 to form a 5-membered ring, or R is hydrogen, methyl, ethyl, or one selected from the group consisting of the following moieties:
2. The compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the following compounds:
Compound 615 N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-aminoacetamide;
Compound 624 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide;
Compound 625 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-phenylpropanamide;
Compound 631 N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-(dimethylamino)acetamide;
Compound 646 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-yl)pyrolidine-2-carboxamide;
Compound 647 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-4-methylpentanamide;
Compound 648 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-cyclohexylpropanamide;
Compound 652 N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide; and Compound 653 (R)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide.
Compound 615 N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-aminoacetamide;
Compound 624 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide;
Compound 625 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-phenylpropanamide;
Compound 631 N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-(dimethylamino)acetamide;
Compound 646 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-yl)pyrolidine-2-carboxamide;
Compound 647 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-4-methylpentanamide;
Compound 648 (S)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-cyclohexylpropanamide;
Compound 652 N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide; and Compound 653 (R)-N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide.
3. The compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-N-(4-(3-(1H-1 ,2,4-triazol- 1 -yl)-4-(3 ,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2- amino-3-methylbutanamide.
4. The compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-N-(4-(3 -(1H- 1 ,2,4-triazol-1-yl)-4-(3 ,4,5 -trimethoxybenzoyl)phenyl)thiazol-2-yl)-2- amino-3-phenylpropanamide.
5. A pharmaceutical composition for inhibiting formation of microtubules, comprising the compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
6. The composition according to claim 5, wherein the composition is useful for treating malignant tumors, viral and bacterial infection, recurrent vascular occlusion, inflammatory diseases, autoimmune diseases or psoriasis.
7. A method for preparing a compound represented by formula 6, comprising reacting a compound 516[ {4-(2-aminothiazol-4-yl)-2-(1H-1,2,4-triazol-1-yl)phenyl} (3,4,5-trimethoxyphenyl)methanone] with a compound represented by formula 3 or 5:
wherein R1' is Fmoc(N-a-9-fluorenylmethoxycarbonyl) group or CH3; R2 is H or CH3;
and R is joined with R2 to forrn a 5-membered ring, or R is hydrogen, methyl, ethyl or one selected from the group consisting of the following moieties:
wherein R1' is Fmoc(N-a-9-fluorenylmethoxycarbonyl) group or CH3; R2 is H or CH3;
and R is joined with R2 to forrn a 5-membered ring, or R is hydrogen, methyl, ethyl or one selected from the group consisting of the following moieties:
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| KR20080027820 | 2008-03-26 | ||
| KR10-2008-0027820 | 2008-03-26 | ||
| PCT/KR2009/001095 WO2009119980A2 (en) | 2008-03-26 | 2009-03-05 | Benzophenone thiazole derivatives useful for inhibiting formation of microtubule and method for producing the same |
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| CA2719243A1 CA2719243A1 (en) | 2009-10-01 |
| CA2719243C true CA2719243C (en) | 2013-06-25 |
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| US (1) | US8362267B2 (en) |
| EP (1) | EP2272845B1 (en) |
| JP (1) | JP5378499B2 (en) |
| KR (1) | KR101069735B1 (en) |
| CN (1) | CN101981029B (en) |
| AU (1) | AU2009229709B2 (en) |
| BR (1) | BRPI0906248B8 (en) |
| CA (1) | CA2719243C (en) |
| DK (1) | DK2272845T3 (en) |
| ES (1) | ES2536794T3 (en) |
| HU (1) | HUE025268T2 (en) |
| MX (1) | MX2010010561A (en) |
| PL (1) | PL2272845T3 (en) |
| PT (1) | PT2272845E (en) |
| WO (1) | WO2009119980A2 (en) |
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| SG10202101116PA (en) * | 2016-07-29 | 2021-03-30 | Chong Kun Dang Pharmaceutical Corp | Compositions for treating liver cancer comprising a vascular disrupting agent |
| US9980953B2 (en) * | 2016-09-26 | 2018-05-29 | Chong Kun Dang Pharmaceutical Corp. | Combined composition for preventing or treating cancer comprising a benzophenone thiazole derivatives as a VDA and topoisomerase inhibitor |
| CN107163011B (en) * | 2017-05-27 | 2019-10-01 | 上海应用技术大学 | 3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin and its preparation method and application |
| WO2019022501A1 (en) * | 2017-07-26 | 2019-01-31 | Chong Kun Dang Pharmaceutical Corp. | Composition for preventing or treating cancer comprising a vascular disrupting agent and immune checkpoint inhibitor |
| KR102216772B1 (en) | 2018-05-18 | 2021-02-17 | 주식회사 종근당 | Composition for preventing or treating cancer comprising a vascular disrupting agent and taxane compound |
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| JP2006519874A (en) | 2003-03-05 | 2006-08-31 | セルジーン・コーポレーション | Diphenylethylene compounds and uses thereof |
| ATE469878T1 (en) * | 2003-07-24 | 2010-06-15 | Leo Pharma As | AMINOBENZOPHENONE COMPOUNDS |
| PL1828148T3 (en) * | 2004-12-13 | 2010-08-31 | Leo Pharma As | Triazole substituted aminobenzophenone compounds |
| KR100932093B1 (en) * | 2006-09-27 | 2009-12-16 | 주식회사종근당 | Benzophenone Derivatives Useful as Inhibitors of Microtubule Formation |
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- 2009-03-05 AU AU2009229709A patent/AU2009229709B2/en active Active
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Also Published As
| Publication number | Publication date |
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| HUE025268T2 (en) | 2016-02-29 |
| EP2272845A2 (en) | 2011-01-12 |
| BRPI0906248A2 (en) | 2016-10-25 |
| EP2272845B1 (en) | 2015-03-04 |
| CA2719243A1 (en) | 2009-10-01 |
| KR20090102639A (en) | 2009-09-30 |
| US20110021582A1 (en) | 2011-01-27 |
| BRPI0906248B8 (en) | 2021-05-25 |
| PL2272845T3 (en) | 2015-08-31 |
| JP5378499B2 (en) | 2013-12-25 |
| ES2536794T3 (en) | 2015-05-28 |
| PT2272845E (en) | 2015-06-01 |
| AU2009229709A1 (en) | 2009-10-01 |
| DK2272845T3 (en) | 2015-05-04 |
| US8362267B2 (en) | 2013-01-29 |
| JP2011515461A (en) | 2011-05-19 |
| AU2009229709B2 (en) | 2011-12-08 |
| MX2010010561A (en) | 2010-10-25 |
| WO2009119980A2 (en) | 2009-10-01 |
| EP2272845A4 (en) | 2014-01-01 |
| CN101981029B (en) | 2014-04-02 |
| BRPI0906248B1 (en) | 2020-01-21 |
| CN101981029A (en) | 2011-02-23 |
| KR101069735B1 (en) | 2011-10-04 |
| WO2009119980A3 (en) | 2009-12-17 |
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